In response to external and internal signals, mammalian cells elicit post-transcriptional changes in gene expression patterns that govern the global cellular response. We are keenly interested in the mechanisms that regulate the expression of proliferative, cell cycle-regulatory, and stress-response proteins. Over the past 17 years, this Project has examined numerous RBPs, noncoding (nc)RNAs, and their influence on gene expression patterns. We have paid close attention to their influence on the stress and proliferative response of cells, two processes that are severely impaired during aging. In the past funding period, we have continued to focus on RBPs implicated in the cellular response to mitogens and stresses, but have expanded substantially into ncRNAs that influence these responses. Since impaired adaptation to mitogens and cell injury underlie various cancer traits (cell proliferation and survival, angiogenesis, invasion, metastasis, and evasion of immune recognition), most studies in this project use cancer cells as the model system. Proliferation and stress response. We have continued to investigate the influence of HuR on cell division. During this review period, we studied several post-transcriptional and post-translational mechanisms controlling HuR expression and function. We found that HuR was mobilized to stress granules (SGs) following exposure to the stress agent arsenite. Unexpectedly, however, this transport was prevented through the activation of Janus kinase 3 (JAK3) by the vitamin K3 analog menadione. JAK3 phosphorylated HuR at tyrosine 200, in turn inhibiting HuR localization in SGs, reducing HuR interaction with targets SIRT1 and VHL mRNAs, and accelerating target mRNA decay. These findings indicate that HuR is tyrosine-phosphorylated by JAK3, and link this modification to HuR subcytoplasmic localization and to the fate of HuR target mRNAs. These findings were reported in Nuc Acids Res (Yoon et al., 2014). Tumorigenesis. The ability of HuR to promote tumorigenic traits continued to be revealed during this review period. One of the most important studies during this review period focused on the ncRNA 7SL, which is upregulated in cancer cells, but its impact upon the cancer phenotype is unknown. We obtained evidence that 7SL formed a partial hybrid with the 3'-untranslated region (UTR) of TP53 mRNA, which encodes the tumor suppressor p53. The interaction of 7SL with TP53 mRNA reduced p53 translation, as determined by analyzing p53 expression levels, nascent p53 translation and TP53 mRNA association with polysomes. Silencing 7SL led to increased binding of HuR to TP53 mRNA, an interaction that led to the promotion of p53 translation and increased p53 abundance. These results, reported by Abdelmohsen et al., (Nuc Acids Res 2014) suggest that the competition between 7SL and HuR for binding to TP53 3'UTR contributes to determining the magnitude of p53 translation, in turn affecting p53 levels and the growth-suppressive function of p53. Our findings further suggest that targeting 7SL may be effective in the treatment of cancers with reduced p53 levels. Additional work during this review period was aimed at characterizing the ncRNAs involved in cancer, proliferation, stress-response, senescence, and other processes relevant to aging. We compiled the literature pertaining to tumor suppressor microRNAs in a review article by Abdelmohsen et al. (2013), appearing in International Journal of Medical Science.